PROJECT SUMMARY Alcohol misuse affects people of all ages, genders, and ethnic groups, and it remains a devastating problem for our Veterans. The effects of alcoholism on the brain are particularly critical because of the potential impact on the facilitation and maintenance of alcohol abuse itself. The newly proposed studies build and expand upon recent findings of abnormalities in brain systems controlling specific emotional and behavioral functions associated with this devastating condition. Long-range objectives are: (1) to understand the nature and cerebral bases of neurobehavioral dysfunction in abstinent long-term alcoholic individuals; (2) to clarify the contributions of altered emotional perception and behaviors to alcohol-related cognitive decline; and (3) to determine the nature and scope of gender differences in any observed deficits and intact skills. Based upon a theoretical framework that views alcoholism-related brain abnormalities as encompassing an interrelated multi-component brain-reward network, the studies will continue to combine neurobehavioral measures with structural and functional brain imaging to provide in vivo correlative information on regional brain differences before, during, and after exposure to emotional stimuli. Modulation of emotional and nonemotional responses also will be measured. Throughout the research, the studies will examine the possibility that despite structural or functional deficiencies in some brain regions of alcoholics, there may be compensatory participation of other brain regions, which allows the affected individuals to maintain behavioral adequacy. Although controversial, evidence indicates gender differences in the effects of alcoholism on the brain may differentially affect emotional perception and reactivity. Therefore, gender-specific compensatory shifts in regional involvement also will be explored. Participants will be abstinent alcoholic men and women, ages 18-55, and nonalcoholic men and women group-matched on age, education, and IQ. Primary regions of interests (ROIs) include prefrontal cortex (and associated white matter connections), and medial temporal areas, which together constitute a neural system intrinsic to emotion, reward, and intentional behaviors. In concert with the use of functional magnetic resonance imaging (fMRI) during emotion- and reward-related tasks, we will conduct structural MRI analyses that include morphometric assessment of brain regions involved in fronto-limbic emotion and reward circuits, and diffusion tensor magnetic resonance imaging (DT- MRI) will be applied to assess coherence of white matter tracts connecting frontal regions with limbic, ventral striatal, and posterior cerebral systems. Neurobehavioral and psychophysiological (electrodermal) measures will be recorded concurrently with central hemodynamic (fMRI) changes in order to examine the coupling between autonomic and central measures of behavior. Overall, one aim is to sharpen distinctions among neurobehavioral sequelae and/or predisposing factors of alcoholism in men and women, and to contribute valuable information about the associated neurobiology of cognitive aspects of emotional and decisional deficits in alcoholism. A corollary aim is to addresses a fundamental need to understand and thereby, to help remediate the behavioral and neuropsychiatric sequelae of alcoholism in male and female Veterans. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Relevance Alcoholism-related disorders are highly prevalent among American Veterans, who also suffer tremendously from associated medical, psychological, and financial problems. In fact, Veterans have nearly two and a half times the lifetime prevalence of alcohol-related disorders than nonveterans. Combat exposure also has been associated with high risk of alcohol misuse, and it is a growing problem among military personnel who have served in Iraq and Afghanistan. Because emotion dysregulation may underlie addictive disorders such as alcoholism, this may, in turn, further alter emotional states in the sufferer. Furthermore, there are demonstrated gender differences in substance abuse treatment needs. Moreover, alcoholism-related abnormalities in brain centers controlling emotional perception and regulation may differ for men and women, and can differentially alter the course of alcoholism directly, by affecting sensitivity to feedback, as well as the ability to make important decisions. The proposed research will address these issues.